Boron(III) bromide-induced ring contraction of 3-oxygenated piperidines to 2-(bromomethyl)pyrrolidines

Tehrani, Kourosch Abbaspour; Syngel, Kris Van; Boelens, Mark; Contreras, Jan; Kimpe, Norbert De; Knight, David W.

doi:10.1016/s0040-4039(00)00191-x

Cited by 32 publications

(8 citation statements)

References 11 publications

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“…Whilst electrophile induced cyclisation of alkenyl imines using molecular bromine has been reported by De Kimpe et al, 9,10 the present work provides an example of this reaction proceeding within a complex molecular framework. Furthermore, participation of a spiroimine unit (rather than a simple imine) in this novel bromine-induced ring expansion reaction provides insight into how the reactivity of a spiroimine moiety may contribute to the toxicity of this marine biotoxin when activated by the presence of an appropriate environmental electrophile.…”

supporting

confidence: 54%

A Novel Bromine-Induced Ring Expansion of the Spiroimine Moiety of the Shellfish Toxin Gymnodimine

Brimble¹,

Robinson²,

Merten³

et al. 2006

Synlett

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Treatment of the shellfish toxin gymnodimine with one equivalent of molecular bromine at -78°C resulted in stereoselective formation of a novel ring-expansion product. Participation of the spiromine unit in this novel bromine-induced ring expansion reaction provides insight into how the reactivity of spiroimine moiety may contribute to the toxicity of this marine biotoxin when activated by the presence of an appropriate environmental electrophile.The marine biotoxin gymnodimine (1) was first isolated from oysters (Tiostrea chilensis) collected at Foveaux Strait in the South Island of New Zealand and was found to exhibit neurotoxic shellfish poisoning in the mouse bioassay. 1 Gymnodimine (1) is produced by the dinoflagellate, Karenia selliformis (syn Gymnodinium selliforme) and its structure was initially elucidated by NMR spectroscopy 1 and later confirmed by X-ray crystallographic analysis. 2 Gymnodimine (1) is a member of the spiroimine group of toxins, which includes the spirolides, 3 pinnatoxins 4 and pteriatoxins. 5 Gymnodimine (1) causes a characteristic rapid death in the intraperitoneal mouse bioassay and belongs to a family of 'fast-acting toxins'. 6 The related compounds, the spirolides, exhibit high oral potency with neurotoxic symptoms and appear to affect the muscarinic acetylcholine receptors in mammalian systems. 3,6,7 Recently, Dragunow et al. 8 investigated the effect of gymnodimine (1) and several chemically modified analogues of gymnodimine on cellular viability. The results of this study indicated that gymnodimine and analogues sensitize cells to an apoptosis inducing agent, okadaic acid. Whether this action is involved in the toxicity of gymnodimine in the mouse bioassay is not known. In order to fully probe the mechanism of action of gymnodimine (1) and related spiroimine-containing toxins, a fundamental understanding of the molecular reactivity of the spiroimine moiety of these molecules is required. We therefore herein report a novel bromine-induced ring expansion of gymnodimine to the 6,9-bicyclic heterocycle 2 triggered by reaction of the spiroimine unit with the electrophilic bromonium ion.It was initially anticipated that treatment of gymnodimine (1) with one equivalent of molecular bromine in wet dichloromethane at -78°C would effect bromination of the three electron-rich olefins present in the structure leaving the unsaturated lactone intact. Of these three electron rich olefins, it was predicted that the C9-C10 olefin would be the most susceptible to attack by an electrophile based on previous reports describing the structure of the macrocycle in solution. 1 Somewhat surprisingly, treatment of gymnodimine (1) with one equivalent of molecular bromine in dichloromethane at -78°C afforded a single product in 81% yield that was established from extensive high field 2D NMR studies to be the ring-expanded bromide 2 rather than a simple dibromide adduct.The proposed mechanism for formation of the ring-expanded product 2 is depicted in Scheme 1. Thus, initial bromination took place at the ...

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confidence: 54%

A Novel Bromine-Induced Ring Expansion of the Spiroimine Moiety of the Shellfish Toxin Gymnodimine

Brimble¹,

Robinson²,

Merten³

et al. 2006

Synlett

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“…De Kimpe et al [33,34,36] investigated the reaction of achiral N-(alkenylidene)alkylamines with different electrophiles, focusing on its regio-and stereochemistry and the further derivatization of the resulting iminium salts 3 with nucleophiles, such as LiAlH 4 , [34] alkoxides [36,50] and cyanides. [51] The formation of five-membered, cyclic, iminium salts (pyrrolinium salts) 3 was observed in most cases.…”

Section: Introductionmentioning

confidence: 99%

Diastereoselective Cyclisation of N‐Alkenylideneamines into 3,4‐Dihydro‐2H‐pyrrol‐1‐ium Halides

Schley

Liebscher

2007

Eur J Org Chem

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Keywords:Diastereoselective cyclisation / Pyrrolin-1-ium salts / Pyrrolidines / Heterocycles / Synthetic methods A number of new chiral 2-(α-bromoalkyl)pyrrolinium salts and 2-(α-selenoalkyl)pyrrolidines were synthesized by the halocyclisation and selenocyclisation, respectively, of N-(alkenylidene)alkylamines and subsequent reduction. These cyclisations were implemented in a diastereomeric fashion for the first time. Substrate control (starting imines possessing chirality in the N-alkyl or the N-alkenyl substituent) and re-

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“…However, similar exposure of the diastereoisomeric iodide 5 to identical conditions gave an inseparable 45:55 mixture of the pyrrolidine and piperidine acetates 9:10 in 82% overall yield. The possible intermediacy of an aziridinium ion in these transformations from participation of the adjacent N-atom is well precedented, 14 with mechanistic studies indicating that the regioselectivity of aziridinium opening is dependent upon the nature of the nucleophile 15 and solvent 16 and both steric and electronic substituent effects. 17 To probe the involvement of an aziridinium ion in this protocol, treatment of iodide 4 with AgBF 4 gave the isolable aziridinium 8 in quantitative yield, which upon treatment with NaOAc in toluene gave acetate 7 as a single diastereoisomer in 70% yield.…”

mentioning

confidence: 99%

Iodine-mediated Ring Closing Alkene Iodoamination with N-Debenzylation for the Asymmetric Synthesis of Polyhydroxylated Pyrrolidines

Davies¹,

Nicholson²,

Price³

et al. 2004

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An iodine-mediated ring closing alkene iodoamination with N-debenzylation protocol provides a direct route for the asymmetric synthesis of polyhydroxylated pyrrolidines from homochiral b-amino acid derivatives.The stereoselective syntheses of pyrrolidines and piperidines are of widespread academic and pharmaceutical interest, both as natural product targets and for potential applications in asymmetric synthesis. Within this expanding field, the synthesis of polyhydroxylated derivatives of these nitrogen heterocycles is of particular interest, as these sugar mimics exhibit a diverse range of biological activities, including potential as anti-HIV candidates 1 and as glycosidase inhibitors. 2 As a result, a range of methodologies for their synthesis has been developed, including manipulation of carbohydrates 3 and the application of asymmetric synthesis. 4 Previous work from this laboratory has shown that the conjugate addition of homochiral lithium amides derived from a-methylbenzylamine to a,b-unsaturated esters provides a general methodology for the asymmetric synthesis of b-amino acids. 5 As an extension of this versatile methodology we report herein a stereoselective iodine-mediated ring closing alkene iodoamination with concomitant N-debenzylation for the asymmetric synthesis of polyhydroxylated pyrrolidine bamino acid derivatives. 6 Conjugate addition of homochiral lithium (R)-N-benzyl-N-a-methylbenzylamide to the a,b-unsaturated acceptor (4S,5R)-1 7 gave b-amino ester (3S,4S,5R)-2 in 88% de, and after purification in 70% isolated yield with >98% de. 8 Treatment of b-amino ester (3S,4S,5R)-2 with iodine in MeCN in the presence of NaHCO 3 gave a chromatographically separable 81:19 mixture of N-benzyl pyrrolidines 4:5 in 63% and 17% isolated yield respectively and as single diastereoisomers in each case, in which ring closure to the pyrrolidine and chemoselective N-deprotection had been effected in a single reaction step. Furthermore, N-a-methylbenzylacetamide (6) was also isolated, whose specific rotation {[a] D 25 -3.8 (c 0.7, CHCl 3 ); lit., 9 [a] D 25 +129.5 (c 1.0, CHCl 3 )} indicated that essentially complete racemisation of the N-a-methylbenzyl stereocentre had occurred during the Ritter reaction. This N-deprotection protocol shows remarkable chemoselectivity, with the selective removal of the N-a-methylbenzyl group in the presence of the N-benzyl group being in direct contrast to the previously reported chemoselective N-debenzylations under oxidative 10 or hydrogenative 11 conditions that have been developed upon similar systems from within this laboratory. The isolation of racemic N-a-methylbenzylacetamide (6) and pyrrolidines 4 and 5 from this reaction manifold is consistent with the mechanism of this transformation involving iodonium ion formation and intramolecular trapping by the tethered tertiary amine to give quaternary ammonium species 3. Preferential S N 1 loss of the N-a-methylbenzyl protecting group from 3 accounts for the remarkable chemoselectivity observed in this reaction, with trapping o...

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Boron(III) bromide-induced ring contraction of 3-oxygenated piperidines to 2-(bromomethyl)pyrrolidines

Cited by 32 publications

References 11 publications

A Novel Bromine-Induced Ring Expansion of the Spiroimine Moiety of the Shellfish Toxin Gymnodimine

A Novel Bromine-Induced Ring Expansion of the Spiroimine Moiety of the Shellfish Toxin Gymnodimine

Diastereoselective Cyclisation of N‐Alkenylideneamines into 3,4‐Dihydro‐2H‐pyrrol‐1‐ium Halides

Iodine-mediated Ring Closing Alkene Iodoamination with N-Debenzylation for the Asymmetric Synthesis of Polyhydroxylated Pyrrolidines

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